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Genetic alterations in prostate cancer

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Abstract

Prostate cancer is the number one malignancy among men. The search for causative factors has proven to be difficult and, accordingly, treatment options for advanced prostate cancer remain limited. However, technologic breakthroughs in the fields of genetics and molecular biology have advanced our understanding of the mechanisms involved in prostate carcinogenesis. The aim of this article is to review the most recent evidence for the role of various genetic insults at specific steps in tumor formation and to suggest potential therapeutic targets.

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References and Recommended Reading

  1. Steinberg GD, Carter BS, Beaty TH, et al.: Family history and the risk of prostate cancer. Prostate 1990, 17:337–347.

    Article  PubMed  CAS  Google Scholar 

  2. Carter BS, Beaty TH, Steinberg GD, et al.: Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci U S A 1992, 89:3367–3371.

    Article  PubMed  CAS  Google Scholar 

  3. Smith JR, Freije D, Carpten JD, et al.: Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 1996, 274:1371–1374.

    Article  PubMed  CAS  Google Scholar 

  4. Gronberg H, Isaacs SD, Smith JR, et al.: Characteristics of prostate cancer in families potentially linked to the hereditary prostate cancer 1 (HPC1) locus. JAMA 1997, 278:1251–1255.

    Article  PubMed  CAS  Google Scholar 

  5. Carpten J, Nupponen N, Isaacs S, et al.: Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nat Genet 2002, 30:181–184.

    Article  PubMed  CAS  Google Scholar 

  6. Rokman A, Ikonen T, Seppala EH, et al.: Germline alterations of the RNASEL gene, a candidate HPC1 gene at 1q25, in patients and families with prostate cancer. Am J Hum Genet 2002, 70:1299.

    Article  PubMed  CAS  Google Scholar 

  7. Casey G, Neville PJ, Plummer SJ, et al.: RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases. Nat Genet 2002, 32:581–583.

    Article  PubMed  CAS  Google Scholar 

  8. Wang L, McDonnell SK, Elkins DA, et al.: Analysis of the RNASEL gene in familial and sporadic prostate cancer. Am J Hum Genet 2002, 71:116–123.

    Article  PubMed  CAS  Google Scholar 

  9. Rennert H, Bercovich D, Hubert A, et al.: A novel founder mutation in the RNASEL gene, 471delAAAG, is associated with prostate cancer in Ashkenazi Jews. Am J Hum Genet 2002, 71:981–984.

    Article  PubMed  Google Scholar 

  10. Hayes RB, Pottern LM, Strickler H, et al.: Sexual behaviour, STDs and risks for prostate cancer. Br J Cancer 2000, 82:718–725.

    Article  PubMed  CAS  Google Scholar 

  11. Zambrano A, Kalantari M, Simoneau A, et al.: Detection of human polyomaviruses and papillomaviruses in prostatic tissue reveals the prostate as a habitat for multiple viral infections. Prostate 2002, 53:263–276.

    Article  PubMed  CAS  Google Scholar 

  12. Xu J, Zheng SL, Hawkins GA, et al.: Linkage and association studies of prostate cancer susceptibility: evidence for linkage at 8p22-23. Am J Hum Genet 2001, 69:341–350.

    Article  PubMed  CAS  Google Scholar 

  13. Cunningham JM, Shan A, Wick MJ, et al.: Allelic imbalance and microsatellite instability in prostatic adenocarcinoma. Cancer Res 1996, 56:4475–4482.

    PubMed  CAS  Google Scholar 

  14. Ishiguro T, Naito M, Yamamoto T, et al.: Role of macrophage scavenger receptors in response to Listeria monocytogenes infection in mice. Am J Pathol 2001, 158:179–188.

    PubMed  CAS  Google Scholar 

  15. Xu J, Zheng SL, Komiya A, et al.: Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. Nat Genet 2002, 32:321–325.

    Article  PubMed  CAS  Google Scholar 

  16. Seppala EH, Ikonen T, Autio V, et al.: Germ-line alterations in MSR1 gene and prostate cancer risk. Clin Cancer Res 2003, 9:5252–5256.

    PubMed  Google Scholar 

  17. Tavtigian SV, Simard J, Teng DH, et al.: A candidate prostate cancer susceptibility gene at chromosome 17p. Nat Genet 2001, 27:172–180.

    Article  PubMed  CAS  Google Scholar 

  18. Takahashi H, Lu W, Watanabe M, et al.: Ser217Leu polymorphism of the HPC2/ELAC2 gene associated with prostatic cancer risk in Japanese men. Int J Cancer 2003, 107:224–228.

    Article  PubMed  CAS  Google Scholar 

  19. Severi G, Giles GG, Southey MC, et al.: ELAC2/HPC2 polymorphisms, prostate-specific antigen levels, and prostate cancer. J Natl Cancer Inst 2003, 95:818–824.

    Article  PubMed  CAS  Google Scholar 

  20. Cancel-Tassin G, Latil A, Valeri A, et al.: PCAP is the major known prostate cancer predisposing locus in families from south and west Europe. Eur J Hum Genet 2001, 9:135–142.

    Article  PubMed  CAS  Google Scholar 

  21. Gibbs M, Chakrabarti L, Stanford JL, et al.: Analysis of chromosome 1q42.2-43 in 152 families with high risk of prostate cancer. Am J Hum Genet 1999, 64:1087–1095.

    Article  PubMed  CAS  Google Scholar 

  22. Xu J, Meyers D, Freije D, et al.: Evidence for a prostate cancer susceptibility locus on the X chromosome. Nat Genet 1998, 20:175–179.

    Article  PubMed  CAS  Google Scholar 

  23. Kibel AS, Faith DA, Bova GS, Isaacs WB: Xq27-28 deletions in prostate carcinoma. Genes Chromosomes Cancer 2003, 37:381–388.

    Article  PubMed  CAS  Google Scholar 

  24. Gibbs M, Stanford JL, McIndoe RA, et al.: Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36. Am J Hum Genet 1999, 64:776–787.

    Article  PubMed  CAS  Google Scholar 

  25. Berry R, Schroeder JJ, French AJ, et al.: Evidence for a prostate cancer-susceptibility locus on chromosome 20. Am J Hum Genet 2000, 67:82–91.

    Article  PubMed  CAS  Google Scholar 

  26. Cancel-Tassin G, Latil A, Valeri A, et al.: No evidence of linkage to HPC20 on chromosome 20q13 in hereditary prostate cancer. Int J Cancer 2001, 93:455–456.

    Article  PubMed  CAS  Google Scholar 

  27. Giovannucci E, Stampfer MJ, Krithivas K, et al.: The CAG repeat within the androgen receptor gene and its relationship to prostate cancer [published erratum appears in Proc Natl Acad Sci U S A 1997, 94:8272]. Proc Natl Acad Sci U S A 1997, 94:3320–3323.

    Article  PubMed  CAS  Google Scholar 

  28. Knoke I, Allera A, Wieacker P: Significance of the CAG repeat length in the androgen receptor gene (AR) for the transactivation function of an M780I mutant AR. Hum Genet 1999, 104:257–261.

    Article  PubMed  CAS  Google Scholar 

  29. Sartor O, Zheng Q, Eastham JA: Androgen receptor gene CAG repeat length varies in a race-specific fashion in men without prostate cancer. Urology 1999, 53:378–380.

    Article  PubMed  CAS  Google Scholar 

  30. Stanford JL, Just JJ, Gibbs M, et al.: Polymorphic repeats in the androgen receptor gene: molecular markers of prostate cancer risk. Cancer Res 1997, 57:1194–1198.

    PubMed  CAS  Google Scholar 

  31. Correa-Cerro L, Wohr G, Haussler J, et al.: (CAG)nCAA and GGN repeats in the human androgen receptor gene are not associated with prostate cancer in a French-German population. Eur J Hum Genet 1999, 7:357–362.

    Article  PubMed  CAS  Google Scholar 

  32. Davis DL, Russel DW: Unusual length polymorphism in human steroid 5 alpha-reductase type 2 gene (SRD5A2). Hum Mol Genet 1993, 2:820.

    Article  PubMed  CAS  Google Scholar 

  33. Reichardt JK, Makridakis N, Henderson BE, et al.: Genetic variability of the human SRD5A2 gene: implications for prostate cancer risk. Cancer Res 1995, 55:3973–3975.

    PubMed  CAS  Google Scholar 

  34. Makridakis NM, Ross RK, Pike MC, et al.: Association of missense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men in Los Angeles, USA. Lancet 1999, 354:975–978.

    Article  PubMed  CAS  Google Scholar 

  35. Hsing AW, Chen C, Chokkalingam AP, et al.: Polymorphic markers in the SRD5A2 gene and prostate cancer risk: a population-based case-control study. Cancer Epidemiol Biomarkers Prev 2001, 10:1077–1082.

    PubMed  CAS  Google Scholar 

  36. Jaffe JM, Malkowicz SB, Walker AH, et al.: Association of SRD5A2 genotype and pathological characteristics of prostate tumors. Cancer Res 2000, 60:1626–1630.

    PubMed  CAS  Google Scholar 

  37. Pearce CL, Makridakis NM, Ross RK, et al.: Steroid 5-alpha reductase type II V89L substitution is not associated with risk of prostate cancer in a multiethnic population study. Cancer Epidemiol Biomarkers Prev 2002, 11:417–418.

    PubMed  CAS  Google Scholar 

  38. Chang BL, Zheng SL, Isaacs SD, et al.: Evaluation of SRD5A2 sequence variants in susceptibility to hereditary and sporadic prostate cancer. Prostate 2003, 56:37–44.

    Article  PubMed  CAS  Google Scholar 

  39. Febbo PG, Kantoff PW, Platz EA, et al.: The V89L polymorphism in the 5 alpha-reductase type 2 gene and risk of prostate cancer. Cancer Res 1999, 59:5878–5881.

    PubMed  CAS  Google Scholar 

  40. Ntais C, Polycarpou A, Ioannidis JP: SRD5A2 gene polymorphisms and the risk of prostate cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2003, 12:618–624.

    PubMed  CAS  Google Scholar 

  41. Gsur A, Bernhofer G, Hinteregger S, et al.: A polymorphism in the CYP17 gene is associated with prostate cancer risk. Int J Cancer 2000, 87:434–437.

    Article  PubMed  CAS  Google Scholar 

  42. Stanford JL, Noonan EA, Iwasaki L, et al.: A polymorphism in the CYP17 gene and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 2002, 11:243–247.

    PubMed  CAS  Google Scholar 

  43. Chang B, Zheng SL, Isaacs SD, et al.: Linkage and association of CYP17 gene in hereditary and sporadic prostate cancer. Int J Cancer 2001, 95:354–359.

    Article  PubMed  CAS  Google Scholar 

  44. Habuchi T, Liqing Z, Suzuki T, et al.: Increased risk of prostate cancer and benign prostatic hyperplasia associated with a CYP17 gene polymorphism with a gene dosage effect. Cancer Res 2000, 60:5710–5713.

    PubMed  CAS  Google Scholar 

  45. Rebbeck TR, Jaffe JM, Walker AH, et al.: Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 1998, 90:1225–1229.

    Article  PubMed  CAS  Google Scholar 

  46. Paris PL, Kupelian PA, Hall JM, et al.: Association between a CYP3A4 genetic variant and clinical presentation in African-American prostate cancer patients. Cancer Epidemiol Biomarkers Prev 1999, 8:901–905.

    PubMed  CAS  Google Scholar 

  47. Lee WH, Morton RA, Epstein JI, et al.: Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. Proc Natl Acad Sci U S A 1994, 91:11733–11737.

    Article  PubMed  CAS  Google Scholar 

  48. Brooks JD, Weinstein M, Lin X, et al.: CG island methylation changes near the GSTP1 gene in prostatic intraepithelial neoplasia. Cancer Epidemiol Biomarkers Prev 1998, 7:531–536.

    PubMed  CAS  Google Scholar 

  49. Nelson WG, DeWeese TL, DeMarzo AM: The diet, prostate inflammation, and the development of cancer. Cancer Metastasis Rev 2002, 21:3–16.

    Article  PubMed  CAS  Google Scholar 

  50. Matsuyama H, Pan Y, Skoog L, et al.: Deletion mapping of chromosome 8p in prostate cancer by fluorescence in situ hybridization. Oncogene 1994, 9:3071–3076.

    PubMed  CAS  Google Scholar 

  51. Vocke CD, Pozzatti RO, Bostwick DG, et al.: Analysis of 99 microdissected prostate carcinomas reveals a high frequency of allelic loss on chromosome 8p12-21. Cancer Res 1996, 56:2411–2416.

    PubMed  CAS  Google Scholar 

  52. Bowen C, Bubendorf L, Voeller HJ, et al.: Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression. Cancer Res 2000, 60:6111–6115.

    PubMed  CAS  Google Scholar 

  53. Bhatia-Gaur R, Donjacour AA, Sciavolino PJ, et al.: Roles for Nkx3.1 in prostate development and cancer. Genes Dev 1999, 13:966–977.

    PubMed  CAS  Google Scholar 

  54. Magee JA, Abdulkadir SA, Milbrandt J: Haploinsufficiency at the Nkx3.1 locus: a paradigm for stochastic, dosage-sensitive gene regulation during tumor initiation. Cancer Cell 2003, 3:273–283. A demonstration that post-pubescent depletion of NKX3.1 results in a prolonged regenerative phase in response to androgen replacement in castrated mice, suggesting that this protein may play a role in proliferative control.

    Article  PubMed  CAS  Google Scholar 

  55. Luo J, Zha S, Gage WR, et al.: Alpha-methylacyl-CoA racemase: a new molecular marker for prostate cancer. Cancer Res 2002, 62:2220–2226.

    PubMed  CAS  Google Scholar 

  56. DeMarzo AM, Meeker AK, Zha S, et al.: Human prostate cancer precursors and pathobiology. Urology 2003, 62(suppl 5A):55. An excellent review regarding the roles of inflammation and atrophy in prostate carcinogenesis.

    Article  Google Scholar 

  57. Dennis LK, Lynch CF, Torner JC: Epidemiologic association between prostatitis and prostate cancer. Urology 2002, 60:78–83.

    Article  PubMed  Google Scholar 

  58. De Marzo AM, Marchi VL, Epstein JI, Nelson WG: Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. Am J Pathol 1999, 155:1985–1992.

    PubMed  Google Scholar 

  59. Nakayama M, Bennett CJ, Hicks JL, et al.: Hypermethylation of the human glutathione S-transferase-pi gene (GSTP1) CpG island is present in a subset of proliferative inflammatory atrophy lesions but not in normal or hyperplastic epithelium of the prostate: a detailed study using laser-capture microdissection. Am J Pathol 2003, 163:923–933.

    PubMed  CAS  Google Scholar 

  60. Kibel AS, Faith DA, Bova GS, Isaacs WB: Loss of heterozygosity at 12p12-13 in primary and metastatic prostate adenocarcinoma. J Urol 2000, 164:192–196.

    Article  PubMed  CAS  Google Scholar 

  61. Guo Y, Sklar GN, Borkowski A, et al.: Loss of the cyclin-dependent kinase inhibitor p27(Kip1) protein in human prostate cancer correlates with tumor grade. Clin Cancer Res 1997, 3:2269–2274.

    PubMed  CAS  Google Scholar 

  62. Freedland SJ, deGregorio F, Sacoolidge JC, et al.: Preoperative p27 status is an independent predictor of prostate specific antigen failure following radical prostatectomy. J Urol 2003, 169:1325–1330.

    Article  PubMed  CAS  Google Scholar 

  63. Yang RM, Naitoh J, Murphy M, et al.: Low p27 expression predicts poor disease-free survival in patients with prostate cancer. J Urol 1998, 159:941–945.

    Article  PubMed  CAS  Google Scholar 

  64. Ben-Izhak O, Lahav-Baratz S, Meretyk S, et al.: Inverse relationship between Skp2 ubiquitin ligase and the cyclin dependent kinase inhibitor p27Kip1 in prostate cancer. J Urol 2003, 170:241–245.

    Article  PubMed  CAS  Google Scholar 

  65. Li J, Yen C, Liaw D, et al.: PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997, 275:1943–1947.

    Article  PubMed  CAS  Google Scholar 

  66. Rubin MA, Gerstein A, Reid K, et al.: Papadopoulos N. 10q23.3 loss of heterozygosity is higher in lymph node-positive (pT2-3,N+) versus lymph node-negative (pT2-3,N0) prostate cancer. Hum Pathol 2000, 31:504–508.

    Article  PubMed  CAS  Google Scholar 

  67. McMenamin ME, Soung P, Perera S, et al.: Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage. Cancer Res 1999, 59:4291–4296.

    PubMed  CAS  Google Scholar 

  68. Feilotter HE, Nagai MA, Boag AH, et al.: Analysis of PTEN and the 10q23 region in primary prostate carcinomas. Oncogene 1998, 16:1743–1748.

    Article  PubMed  CAS  Google Scholar 

  69. Whang YE, Wu X, Suzuki H, et al.: Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci U S A 1998, 95:5246–5250.

    Article  PubMed  CAS  Google Scholar 

  70. Kim MJ, Cardiff RD, Desai N, et al.: Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis. Proc Natl Acad Sci U S A 2002, 99:2884–2889. A demonstration that multiple genetic alterations can have accelerated carcinogenic effects.

    Article  PubMed  CAS  Google Scholar 

  71. DiCristofano A, De Acetis M, Koff A, et al.: Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse. Nat Genet 2001, 27:222–224.

    Article  CAS  Google Scholar 

  72. Visakorpi T, Kallioniemi AH, Syvanen AC, et al.: Genetic changes in primary and recurrent prostate cancer by comparative genomic hybridization. Cancer Res 1995, 55:342–347.

    PubMed  CAS  Google Scholar 

  73. Cher ML, Bova GS, Moore DH, et al.: Genetic alterations in untreated metastases and androgen-independent prostate cancer detected by comparative genomic hybridization and allelotyping. Cancer Res 1996, 56:3091–3102.

    PubMed  CAS  Google Scholar 

  74. Alers JC, Krijtenburg PJ, Rosenberg C, et al.: Interphase cytogenetics of prostatic tumor progression: specific chromosomal abnormalities are involved in metastasis to the bone. Lab Invest 1997, 77:437–448.

    PubMed  CAS  Google Scholar 

  75. Jenkins RB, Qian J, Lieber MM, Bostwick DG: Detection of cmyc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization. Cancer Res 1997, 57:524–531.

    PubMed  CAS  Google Scholar 

  76. Sato K, Qian J, Slezak JM, et al.: Clinical significance of alterations of chromosome 8 in high-grade, advanced, nonmetastatic prostate carcinoma. J Natl Cancer Inst 1999, 91:1574–1580.

    Article  PubMed  CAS  Google Scholar 

  77. Ellwood-Yen K, Graeber TG, Wongvipat J, et al.: Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell 2003, 4:223–238.

    Article  PubMed  CAS  Google Scholar 

  78. Reiter RE, Gu Z, Watabe T, et al.: Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer. Proc Natl Acad Sci U S A 1998, 95:1735–1740.

    Article  PubMed  CAS  Google Scholar 

  79. Reiter RE, Sato I, Thomas G, et al.: Coamplification of prostate stem cell antigen (PSCA) and MYC in locally advanced prostate cancer. Genes Chromosomes Cancer 2000, 27:95–103.

    Article  PubMed  CAS  Google Scholar 

  80. Gu Z, Thomas G, Yamashiro J, et al.: Prostate stem cell antigen (PSCA) expression increases with high Gleason score, advanced stage, and bone metastasis in prostate cancer. Oncogene 2000, 19:1288–1296.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Urology, David Geffen School of Medicine, University of California at Los Angeles, 650 Charles East Young Drive, Room 66-134 CHS, 90095, Los Angeles, CA, USA

    Robert E. Reiter MD

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  1. Jonathan L. Chin MD
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Chin, J.L., Reiter, R.E. Genetic alterations in prostate cancer. Curr Urol Rep 5, 157–165 (2004). https://doi.org/10.1007/s11934-004-0032-8

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